The present invention relates to a citral acetal from which citral is sustainedly released and to a perfume composition comprising the citral acetal useful as an ingredient incorporated into toiletries and cosmetics. The present invention also relates to an inhibitor of leucine dehydrogenase (referred to hereinafter as LDH) involved in a metabolic pathway of isovaleric acid as a component in body smell and to a deodorant, cosmetics and a skin agent for external application, comprising the LDH inhibitor.
Citral is a perfume having a strong lemon-like aroma contained in natural lemon oil, lemon-grass oil etc., but it is highly volatile and instable to air, sunrays and alkalis, thus hardly sustaining its aroma. To solve this problem, citral dimethyl acetal and citral diethyl acetal have been used, but these compounds possess not lemon aromas but neroli-like citrus green aromas, and do thus not possess the lemon-like aroma of citral. Further, JP-A 11-513742 (WO97/34986) discloses a method of sustainedly releasing citral by converting it into acetals having molecular weights of 350 or more, for example into di-geranyl citral acetal and then hydrolyzing these acetals to release citral sustainedly, but these are high-molecular compounds to which purification techniques such distillation cannot be applied, and perfumes formed therefrom are geraniol and citral, thus making it difficult to reproduce the lemon-like aroma unique to citral. Against these problems, U.S. Pat. No. 5378468 describes that citral is sustainedly released by hydrolysis of citral propylene glycol acetal using propylene glycol having a weak aroma, but it was recognized that this acetal itself is volatile and has a green aroma, thus inhibiting the lemon aroma unique to citral.
Meanwhile, various techniques of suppressing body smell have been developed for inclinations toward cleanliness in recent years. In particular, use of antimicrobial agents and bactericides can be mentioned as the most popular method of suppressing body smell from of old. This method is a method of killing bacteria present on the skin, and can be easily completed thereby giving a feeling of significant effect. However, some bacteria inhabiting on the skin take responsibility for the barrier function of the skin, and it was also reported that the method of killing all bacteria is unfavorable for the human body in the long run, and therefore the antimicrobial agents and bactericides came to be avoided. U.S. Pat. No. 5626852 describes that citral is sustainedly released by hydrolysis of citral propylene glycol acetal using propylene glycol having a weak aroma.
An object of the present invention is to provide a citral acetal capable of sustaining a lemon aroma unique to citral, as well as a perfume composition comprising the same. Another object of the present invention is to provide an LDH inhibitor capable of suppressing unpleasant human body smell by enzyme inhibition not harmful to the human body, that is, by inhibiting enzymatic formation of isovaleric acid regarded as one substance causing unpleasant body smell. The invention then provides a deodorant, cosmetics and a skin agent for external application, comprising the LDH inhibitor.
Under these circumstances, the present inventors found that an acetal of citral with a specific glyceryl ether can be easily purified and can, upon hydrolysis, sustainedly release a lemon aroma unique to citral, and also that this citral acetal has an activity of inhibiting LDH derived from bacteria living on the skin, for example Bacillus bacteria, involved in a pathway of forming isovaleric acid regarded as one substance causing unpleasant human body smell, and the present invention was thereby completed.
That is, the present invention provides a citral acetal represented by formula (1) (referred to hereinafter as citral acetal (1)), a perfume composition comprising citral acetal (1), an LDH inhibitor comprising citral acetal (1), a deodorant, cosmetics and a skin agent for external application, comprising said LDH inhibitor. 
wherein the wavy line represents a cis form, trans form or a mixture thereof and R represents a C1 to C9, linear or branched alkyl group.
The citral acetal of the invention is a reaction product of citral and a glycerin alkyl-monoether. The alkyl may have 1 to 9 carbon atoms.
The invention further provides a leucine dehydrogenase (LDH) inhibitor composition comprising the citral acetal compound as above and a carrier. It moreover provides a leucine dehydrogenase (LDH) inhibitor composition comprising the citral acetal compound as above and a perfume, a deodorant, a cosmetic or a skin agent for external application.
The invention then provides a method of inhibiting leucine dehydrogenase (LDH) on the human skin, which comprising applying an effective amount of the citral acetal compound as above onto the human skin.
The invention provides a method of sustainedly releasing an aroma of citral, which comprises applying an effective amount of the above defined citral acetal compound to a place (locus or spot) where the aroma of citral is desired.
The citral acetal (1) can be produced by reacting citral with a glyceryl ether represented by formula (2) (referred to hereinafter as glyceryl ether (2)) according to a conventional method, for example a method described in xe2x80x9cJikken Kagaku Kozaxe2x80x9d (Course on Experimental Chemistry), 4th ed., vol. 20, p. 245.
CH2(OH)CH(OH)CH2ORxe2x80x83xe2x80x83(2) 
wherein R has the same meaning as defined above.
The glyceryl ether (2) is the one containing 4 to 12 carbon atoms, and examples thereof include methyl glyceryl ether, ethyl glyceryl ether, n-propyl glyceryl ether, isopropyl glyceryl ether, n-butyl glyceryl ether, n-pentyl glyceryl ether, isopentyl glyceryl ether, n-hexyl glyceryl ether, 2-ethyl hexyl glyceryl ether, n-heptyl glyceryl ether, n-octyl glyceryl ether, n-nonyl glyceryl ether etc. The glyceryl ether (2) is used preferably in an amount of 0.5- to 5.0 times as many moles as citral, more preferably 1.0- to 2.0 times.
As the catalyst for reaction of citral with glyceryl ether (2), use can be made of an inorganic acid such as hydrochloric acid, an organic acid such as p-toluenesulfonic acid, citric acid or tartaric acid, and a catalyst carrying sulfonic acid, such as Amberlite 15, among which a mild acid such as citric acid or tartaric acid is preferably used. The catalyst is used preferably in an amount of 0.0001- to 0.5 time as many moles as citral, more preferably 0.001- to 0.1 time, the most preferably 0.002-to0.05 time. This reaction is an equilibrium reaction so that for shifting the equilibrium to the side of acetal, the reaction may be carried out either while removing water through azeotropic distillation with a solvent such as benzene, toluene, cyclohexane, hexane or petroleum ether, or in the presence of a dehydrating agent such as magnesium sulfate. When the dehydrating agent is used, it may be used in an amount of 1- to 2 times as many moles as the formed water. The solvent is used preferably in an amount of 0.5 to 20 times as much weight as citral, more preferably 1 to 10 times.
The reaction temperature is preferably 30 to 150xc2x0 C., more preferably 50 to 100xc2x0 C. The reaction time is varied depending on reaction conditions, but usually the reaction is finished in 6 to 60 hours. After the reaction is finished, the desired citral acetal is obtained from the reaction solution by techniques such as neutralization, filtration, distillation and extraction. If necessary, the product is further purified by conventional methods such as silica gel chromatography, distillation etc.
The citral acetal (1) can maintain a lemon aroma unique to citral for a prolonged period of time. Further, the citral acetal (1) has an activity of inhibiting LDH derived from bacteria living on the skin, such as Bacillus bacteria, involved in a pathway of forming isovaleric acid regarded as one substance causing unpleasant human body smell, and thus the citral acetal (1) is useful as an LDH inhibitor.
The perfume composition of the present invention comprising citral acetal (1) may comprise at least one kind of citral acetal (1) , or known perfume ingredients (e.g., perfume ingredients described in xe2x80x9cGosei Koryo, Kagaku to Shohin Chishikixe2x80x9d (Synthetic Perfumes, Chemistry and Commodity Knowledge), first ed., authored by Genichi Indo, Mar. 6, 1996, published by Kagaku Kogyo Nipposha) blended with at least one kind of citral acetal (1). Although the content of citral acetal (1) in the perfume composition of the present invention is varied depending on the type of composition and the type of intended blended perfume, the content of citral acetal (1) in the composition is preferably 0.01 to 90% by weight, particularly preferably 0.1 to 50% by weight. If necessary, other additives for example an antioxidant selected from phenols such as 2,6-di-tert-butyl hydroxy toluene (BHT) and 2(3)-tert-butyl-4-hydroxy anisole (BHA), hydroquinone or analogues thereof such as tert-butyl hydroquinone (TBHQ), anti-oxidants such as tocopherols and a pH regulator selected from organic acids such as fatty acid, citric acid, tartaric acid and hexahydrophthalic acid and/or salts thereof, inorganic acids such as phosphoric acid and/or inorganic salts such as phosphate can be compounded into the perfume composition of the present invention insofar as the effect of the present invention is deteriorated.
The citral acetal (1) of the present invention can not only maintain a lemon aroma unique to citral for a prolonged period of time but also has the activity of inhibiting LDH and inhibit formation of isovaleric acid regarded as one substance causing human unpleasant smell. Accordingly the citral acetal (1) can, singly or in combination with other ingredients, be used as a component in soap, shampoos, rinses, detergents, cosmetics, deodorants, aromatics, bathing agents, coloring agents, hair colors, antimicrobial agents, anti-fungal agents, dehumidifying agents, bedclothes, towels, clothing, tissue, toilet sand for pets, chewing gum, facial packs, clay compositions for handcrafts, absorbents, cosmetics for massage, coatings, agrochemicals, medicines and ink.
A deodorant containing the LDH inhibitor of the present invention comprising the citral acetal (1) can sustainedly control unpleasant body smell without killing skin inhabitant bacteria involved in maintaining the barrier function of the skin. That is, isovaleric acid regarded as one substance causing unpleasant human body smell is formed from leucine contained in sweat via metabolism by bacteria inhabiting on the skin, such as Bacillus bacteria, and the citral acetal (1) can inhibit bacterial formation of isovaleric acid from leucine, thus certainly controlling unpleasant body smell.
The content of the citral acetal (1) in the deodorant of the present invention is preferably 0.1 to 20% by weight, more preferably 0.5 to 10% by weight.
Further, the LDH inhibitor of the present invention can be used as pharmaceutical preparations such as cosmetics, pharmaceutical preparations for external application (e.g. skin agents for external application) or non-medical preparations, for example in the form of cream, milky lotion, lotion, powder, spray or stick.
For use as cosmetics, medicines for external application or non-medical preparations, the content of citral acetal (1) therein is preferably 0.01 to 20% by weight, more preferably 0.1 to 10% by weight and most preferably 0.5 to 5% by weight.
The resulting cosmetics, medicines for external application or non-medical preparations can be combined arbitrarily with a wide variety of ordinarily used ingredients, for example cosmetic ingredients such as generally used oils, surfactants, alcohols, chelating agents, pH adjusting agents, preservatives, thickeners, pigments and perfumes, as well as UV absorbers, whiteners, wrinkle improvers, humectants, skin-secretion inhibitors, softeners, collagen-protecting agents, efficacious agents, antioxidants and solvents to manufacture the intended preparations.
By applying the cosmetics and skin agents for external application according to the present invention onto sites such as legs, sides, heads, genitals etc. where unpleasant smell can easily occur, occurrence of unpleasant smell can be regulated. The amount of the present cosmetics or skin agents for external application used, though varied depending on the content of citral acetal (1), is preferably 1 to 20 mg/cm2 skin in the case of liquid preparation or 1 to 50 mg/cm2 skin in the case of solid preparation.